BAY1436032 in Patients With Mutant IDH1(mIDH1) Advanced Acute Myeloid Leukemia (AML)

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT03127735

Collaborator

(none)

Enrollment

Locations

Arm

Actual Duration (Months)

2.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To determine the maximum tolerated and / or recommended Phase II dose of oral mutant IDH1 (mIDH1) inhibitor BAY1436032 and to characterize its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy in patients with mIDH1-R132X advanced acute myeloid leukemia (AML)

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute	Drug: BAY1436032	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

27 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated and / or Recommended Phase II Dose of Oral Mutant IDH1 (mIDH1) Inhibitor BAY1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Efficacy in Patients With mIDH1-R132X Advanced Acute Myeloid Leukemia (AML)

Actual Study Start Date :

Jun 14, 2017

Actual Primary Completion Date :

Dec 6, 2018

Actual Study Completion Date :

Mar 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BAY1436032 Dose escalation: Various doses of study drug will be tested on a small number of patients/dose with the goal of identifying the most appropriate dose(s) for further evaluation in dose expansion. The MTD of the study drug may or may not be identified. It is anticipated that 3-4 patients will be treated at each dose of study drug to be tested and that 15-20 total patients will be treated in this part of the trial. Dose expansion: Up to 2 different doses of study drug will be tested on up to 30 patients/dose with the goal of identifying the most appropriate RP2D for further clinical development. The doses to be evaluated in this part of the trial will be selected based on information obtained during dose escalation.	Drug: BAY1436032 BAY1436032 administered continuously as a single agent dosed twice a day orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with BAY1436032 until disease progression, development of other unacceptable toxicity or Investigator discretion.

Arm

Intervention/Treatment

Experimental: BAY1436032

Dose escalation: Various doses of study drug will be tested on a small number of patients/dose with the goal of identifying the most appropriate dose(s) for further evaluation in dose expansion. The MTD of the study drug may or may not be identified. It is anticipated that 3-4 patients will be treated at each dose of study drug to be tested and that 15-20 total patients will be treated in this part of the trial. Dose expansion: Up to 2 different doses of study drug will be tested on up to 30 patients/dose with the goal of identifying the most appropriate RP2D for further clinical development. The doses to be evaluated in this part of the trial will be selected based on information obtained during dose escalation.

Drug: BAY1436032

BAY1436032 administered continuously as a single agent dosed twice a day orally on Days 1 to 28 of a 28-day cycle. Patients may continue treatment with BAY1436032 until disease progression, development of other unacceptable toxicity or Investigator discretion.

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) or RP2D of BAY1436032 [Within first 4 weeks of first dose]
If the MTD is not reached during dose escalation, the primary variable will be the recommended phase 2 dose (RP2D) of BAY1436032
Number of participants with Adverse Events as a Measure of [Up to 12 weeks]
As a measure of safety and tolerability

Secondary Outcome Measures

Objective efficacy response [Up to 12 weeks]
Response assessment for AML in this study will be based on the modified Cheson criteria. The following categories are used to capture the investigator's AML response evaluation: Complete remission (CR) Morphologic CR with CRh (morphologic CR with incomplete hematological recovery) and the response category CRp (morphologic CR with incomplete platelet recovery) Partial remission (PR) Response categories for morphologic leukemia-free state (MLFS), stable disease and progressive disease Progressive disease
Duration of response [Up to 12 weeks]
Efficacy data
Event-free survival (EFS) [Up to 12 weeks]
EFS defined as time from start of treatment to treatment failure, relapse, or death due to any cause.
Change of 2 hydroxyglutarate (2-HG) level obtained at baseline and post-baseline [Up to 12 weeks]
Assess pharmacodynamic (PD) effects and evidence of clinical efficacy associated with BAY 1436032 administration in patients. Change from baseline and percent change from baseline will be calculated.
Cmax (maximum observed drug concentration in plasma after a single dose) [Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hour post-dose (each cycle is 28 days)]
As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated.
AUC(0-8) (AUC from time 0 to 8 h after a single dose) [Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hour post-dose (each cycle is 28 days)]
As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated.
AUC(0-12) (AUC from time 0 to 12 h after a single dose) [Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hour post-dose (each cycle is 28 days)]
if feasible
Cmax,md (Cmax after multiple doses) [Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 12 hour post-dose on Day 15; (each cycle is 28 days)]
As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated.
AUC(0-8)md (AUC from time 0 to 8 h after multiple doses) [Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hour post-dose on Day 15; (each cycle is 28 days)]
As a secondary objective of this study evaluate the pharmacokinetics (PK) of BAY 1436032 in patients. PK parameters normalized for dose and / or dose and body weight will be calculated.
AUC(0-12)md (AUC from time 0 to 12 h after multiple doses) [Pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hour post-dose on Day 15; (each cycle is 28 days)]
if feasible

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with advanced AML that harbors IDH1 mutation
Patients are relapsed from or refractory to at least 1 previous line of therapy
Good kidney and liver function
Male or female patients
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Women must have a negative serum pregnancy test within 7 days prior to the first dose of study drug or be surgically or biologically sterile or postmenopausal

Exclusion Criteria:

Previously treated with any prior mIDH1 targeted therapy
Extramedullary disease only
History of clinically significant or active cardiac disease
Active clinically significant infection
Unresolved chronic toxicity of previous AML treatment
Taking known strong cytochrome P450 (CYP) 2C8 inducers or inhibitors
Pregnancy or breast-feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Montefiore Medical Center	Bronx	New York	United States	10467-2490
2	Roswell Park Comprehensive Cancer Center	Buffalo	New York	United States	14263-0001
3	Mount Sinai Medical Center	New York	New York	United States	10029
4	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
5	Ohio State University	Columbus	Ohio	United States	43210
6	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
7	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
8	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
9	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg	Germany	69120
10	Medizinische Hochschule Hannover (MHH)	Hannover	Niedersachsen	Germany	30625
11	Universitätsklinikum Leipzig AöR	Leipzig	Sachsen	Germany
12	Universitätsklinikum Charite zu Berlin	Berlin		Germany	12200
13	Universitätsklinikum Hamburg Eppendorf (UKE)	Hamburg		Germany	20246